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Decreasing Sensitivity to Cytotoxic Agents Parallels Increasing Tumorigenicity in Human Fibroblasts¹

Paterson Institute for Cancer Research, Christie Hospital and Holt Radium Institute, Wilmslow Road, Manchester, M20 9BX United Kingdom

Human embryo fibroblasts of common genetic origin but exhibiting a range of phenotypes from normal to aggressively tumorigenic have been used to study resistance to the cytotoxic drugs methotrexate and N-(phosphonacetyl)-L-aspartate. Measurement of the intrinsic sensitivities of these cells to the two drugs in standard survival assays, in normal fetal bovine serum, showed increasing resistance to parallel increasing tumorigenicity. Tumor cells were totally resistant to 10 mM N-(phosphonacetyl)-L-aspartate whereas the 50% lethal dose for methotrexate for the tumor cells was 500 nM compared with 50 nM for the normal diploid parent cell line. The difference in resistance between the immortal and tumorigenic cell lines was eliminated for both methotrexate and N-(phosphonacetyl)-L-aspartate, when the experiments were repeated in the presence of dialyzed fetal bovine serum, but could be restored by the addition of either hypoxanthine (100 µM) or uridine (10 µM). This suggested an important role for the salvage pathways of purine and pyrimidine biosynthesis in the increased resistance of the more tumorigenic cell lines. The implications of these data in relation to cancer chemotherapy will be discussed.

¹ This work was funded by the Cancer Research Campaign.

² Present address: Department of Surgery, University of Liverpool, Liverpool, L69 3BX United Kingdom.

Received 8/ 2/90. Accepted 1/24/91.

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